Autoimmune diseases (rheumatoid arthritis, multiple sclerosis, ulcerative colitis, autoimmune uveitis and many others) are diseases in which the immune system does not tolerize self structures of the body, but attacks them like an intruding pathogen. Consequently, body tissue is damaged or even destroyed and pain and physical defects occur (e.g., stiff joints in rheumatoid arthritis; general motion inhibition, incontinence, and speech disability in multiple sclerosis; severe diarrhea, nutritional defects and gut perforation with fatal outcome in ulcerative colitis; in uveitis impaired visual acuity, which can even lead to blindness).
Uveitis is an intraocular inflammation which affects iris, ciliary body vitreous, retina and/or the choroid. With the iris involved inflammation is often painful and can lead to loss of pupillary reaction through iris synechia at its front with the cornea and/or with the lens at its back. Cellular precipitates on the inner side of the cornea and the lens as well as cellular infiltrates in the anterior chamber and the vitreous of the eye, sometimes followed by the development of hazy membranes, which stretch through the vitreous or lay on the retina like a curtain, impair visual acuity. Signs of inflammation of retina and choroid are edema, cellular infiltrates and, in later stages, atrophic changes. Not rarely are the retinal vessels involved in the inflammation. Edematous swellings of the optic nerve papilla can additionally lead to the disturbance of the neuronal processing of light perception. While the described phenomena are partially reversible, destruction of the retinal architecture is an irreversible event, which leads to a lasting impairment of visual acuity and even to blindness.
The described uveitis symptoms can be associated with other autoimmune diseases, e.g., rheumatic diseases or post infectious. The inflammation is initiated by the immune system and other cells are involved in its further course.
In most cases autoimmune diseases are chronic, either relapsing or permanently progressive. In rare cases the tissues, which have been destroyed by the immune system, can be regenerated. If nerve tissue is involved, like in multiple sclerosis or uveitis, a regeneration is not possible. The causes of these autoimmune diseases are mostly unknown, in some cases infections are suspected, which misguide the immune system.
Conventional therapies, that are initiated in cases of immune diseases, target not only the self reactive (xe2x80x9cautoaggressivexe2x80x9d) part of the immune system, but generally suppress immunoreactive cells, which should serve in the defense of invaded pathogens or tumor cells. Besides an impaired general immune defense and the probable development of tumors, conventional therapies with immuno suppressive agents like steroids, cyclosporin A and cytotoxic agents have also many non-immunologic and sometimes life threatening side effects.
In many autoimmune diseases an inherited predisposition is suspected on the grounds of statistical correlations of the disease with certain histocompatibility antigens (HLA, originally described as transplantation antigens). As a mechanism, it is postulated that the immune system confuses pathogen antigens (bacteria, virus) with self HLA-antigens.
Over the last years many attempts have been undertaken to interfere with the regulation of the immune system in order to reinstitute the normal balance of self tolerance and pathogen defense. Amongst others, attempts have been made to induce an immunologic tolerance via xe2x80x9cimmunologically privilegedxe2x80x9d sites of the organism. One example of a privileged site is the mammalian gut, which can be used to induce tolerance (xe2x80x9coral tolerancexe2x80x9d) to protein molecules (xe2x80x9cantigensxe2x80x9d). This mechanism supposedly prevents, that an immune reaction against digested food is continuously generated. The oral administration of xe2x80x9cautoantigensxe2x80x9d (self proteins, against which the aggressive immune response is directed in the case of autoimmune diseases), can therefore induce tolerance, i.e., non-responsiveness to self tissue, even if the site of autoaggression, which is the affected tissue, is spatially far distant from the gut. Oral tolerance induction is a form of immunosuppression, which is highly specific, i.e., the immune reaction affects only the implied antigen. Therefore side effects comparable to those in general immunosuppression are not to be expected. Undesired pharmacological-toxicological effects have not yet been observed in oral applications of autoantigens and are not expected.
The autoantigens are known in some autoimmune diseases and can therefore be used for specific therapies. In some cases there is only one antigen against which the immune reaction is directed (collagen II in rheumatoid arthritis, insulin in diabetes), in the case of autoimmune uveitis two proteins from the photoreceptor layer of the eye are known, which can induce uveitis in the animal model and against which an immune response can be detected in uvietis patients.
These are the retinal S-antigen and the interphotoreceptor-retinoid-binding protein (IRBP). Within these proteins are certain sections (epitopes), which also can induce uveitis if applied as peptides. An experimental uveitis induced by these means can be prevented, if S-antigen, IRBP or peptides thereof are applied orally (oral tolerance). (See, e.g., Thurau, S. R., Chan, C.-C., Suh, E., Nussenblatt, R. B.: Induction of oral tolerance to S-antigen induced experimental autoimmune uveitis by a uveitogenic 20 mer peptide. J. Autoimm. 4: 507-516 (1991). This and the other paper and patent cited herein arm hereby incorporated in their entireties by reference.)
The provision of protein antigens is associated with major difficulties. Moreover, there are a number of disadvantages:
1) Generally the antigen must be isolated from natural tissues. During the process infections (viruses, viroids, bacteria) or transfections with (retro)viral or bacterial DNA probably occur.
2) The antigen can at best with great expense be synthesized genetically.
3) In individual cases, long-term storage of proteins like protein antigens can be difficult. In unfavorable cases, even costly storing conditions can guarantee stability, activity and effectiveness of a protein only for a short time period.
4) The risk of developing an allergy like food allergy or contact allergy is increased with protein antigens, because of a crosslinking on cell surfaces. This is especially important in patients with autoimmune diseases, since there is an increased number of patients with allergies.
The invention will address and solve these problems.
The problem will be addressed and solved by a peptide as described in the claims.
The invention refers on the one hand to a peptide consisting of 7 to 30 amino acid residues with the sequence
A-Leu-B-Ser-C-Thr-Ala-Ala-D (SEQ ID NOS. 1 and 18 to 24),
wherein B and C are each an amino acid or amino acids and A and D are each monomeric or polymeric organic groups.
In addition it has been established that a peptide, which is extended carboxyterminally by the two amino acids, aspartic acid and glutaric acid, compared to the aforementioned core sequence -Leu-B-Ser-C-Thr-Ala-Ala- (residues 2 to 8 of SEQ ID NO: 1), has also outstanding therapeutic features.
Accordingly an additional claim of the invention is a peptide consisting of 9 to 30 amino acids with the sequence
A-Leu-B-Ser-C-Thr-Ala-Ala-Asp-Glu-D (SEQ ID NOS. 2 and 25 to 31),
wherein again B and C are each in amino acid or amino acids and A and D are each monomeric or polymeric organic groups.